Substituted hydrofluorene carboxylic acids



Patented Jan. 10, 1950 SUBSTITUTED HYDROFLUORENE CARBOXYLIC'ACIDS Karl MiesherjRielien, and Georg .Anner, Basel, Switzerland, assignors to. Ciba Pharmaceutical U Products, 'Inc., Summit, N. J

1 .No. Drawing. 1 :Application rseptember 911, 31947,;

Serial-1N0. 773,494.- 20,1946

' This invention relates" to the manufacture of hydrofiuoren'2 -'car,b'ory1ic' acids, which ',c0ntain in the "1-positionfaf'phenolichydroxylgroup. and in each of the I and 2=positions a-hydrocarbon radical, for example," T7-hydroxy-1.:2- d'ialk,yltetrahydrOfluorene-Z-'carboxylic acids or ls-hydroxy 5 1' :2 dialliyl-hexahydrofluorenea2 carboxylic" acids,'..'and .deri'vatives of such acids,

4 Glai'ms. (Cl."260'469) especially e'stersand ethersthereof.- Thecompounds" of this new group unexpectedly A exhibit an "extraordinarily high estrogenic activity win rats", when: administered parenterally wor orally. Thus, for example, the threshold value for 7-- methoxy L 2 methyl-lethyl -l :224 tetrahydrounease-caravan (acid "is l -2 y;-,whenv administered" in bicarbonate solution to castrated female rats in a' single 7 dose-either subcutaneously or by the stomach. Inthesame animals -l-.mil-ligrain, whether :administered.subcutaneously or-by the stomach, gproducesan estrus lasting about- 10 days. I I

The high estrongenic activity of certain hydrophenanthrene'fl-carboxylic acids and derivatives thereof is known (compare Mi'sch'er and co- Workers; Helvetica Chemica Acta, vol. 27, page 1727 [1945] aloe. cit. vol'. 29, pages-586, 1071, 1231, 1889 and 1895 [19461;Experientia, vo1:"2, page ,409

[1946]. However, this activity appears to be con-'- nected with the intact phenanthrene structure, and is completely lost when the 6-membered ring carryingthe carboxyl group is contracted to a 5- membered ring (compare, Billeter and .Miescher, Helvetica" 'Chimica Acta, vol. 29, page"859-l 19426] The new hydrorifludrene-Z-carboxylic acids and their derivatives are made byreacting a ls-ketohydrofiuorene,-w-hich contains in the2-position'a functionally converted carboxyl group in addition" to a hydrocarbon radical and in the 7-position a free phenolic hydroxyl group or a substituent convertible into such a group, with an organ'icemetallic compound appropriate" for introducing a hydrocarbonradical into the l-position, eliminating the newly formedtertiary hydroxyl group directly" or indirectly, and, if desired, converting theifunctionally converted carboxyl group in the 2-posi tion into a free carboxyl group and/or converting for example, derived from 1:223:4-tetrahgdroe fluorenes or 1 :2 :-3 :4 10 ll-hexahydrofiuo'renes, which contain in the l -position a keto-group; in

the 2-position'a hydrocarbon radical, for example,

an alkyl radical, such as a methyl, ethyl or propyl radical, oran' alkeny'l'radical, for example, an allyl radical or an aralkyl, for example, a benzyl radi- Switzerland December :3. cal, [and also a, functionally converted carlgqxyl r up, o exampl ,.an r.ile or c' dlam de roup, especiallyan esterified carboxyligroup, "for exam ple, a carbomethoxy carbethoxy or carbobenzy loxygroup; and in theffl-posi-tjiona free phenolic hydroxyl group or a substituent convertible ,into such a .group, for .example by hydrolysis. The latter substituentrnamfor example, be a.hy d ro xyl group etherified with meth nol. et anql a phenol, a benzyl alcohol or thedike, or este'ri fied with an organic. or inorgani --acid,:such.as acetic, propionic, benzoicrphosphoricor sulfuric. acid or it maybe an aminogroun-t The starting ,n aty rial may, have any desired, steric; configuration and may containvfurther substituenta r In orderto introduceinto the l positon a hy drocarbon radical, forgexample, an I sue-has methyl, ethyl or prqpy-lwn alkenyl -radical such as allyl, anaralkylredifia tsuchas bengy l,,or an alkinyl radical -suc h ethinyl the starting materialis first reactedg-withythe; appropriate-are gano-metallic compound, for example, with an organo-magnesium halide or an organo-zlnc halide, an alkyl-alkali such as sodium ethyl or alkinyl-alkalicompoundsuch as sodium or potassium acetylide; IFrom thezresulting tertiary alcohO1,"i'f desired-after hydrogenating any side chain multiple bonds, the -newly formed tertiary hydroxyl group is eliminated directly or indirectly. This may be brought about, for example, with the formation ,of a carbon-to-carbon double bond. For this purpose, for example, water is split oif directly or thehydroxyl group is first exchanged for halogen or anotherester residue or an ether residue. Then the hydroxyl group so converted may be eliminated, for, example by the action of heat or by treatment wyithan agent capable of splitting off an acid or an alcohol. The splitting off of the tertiary hydroxyl group, which results from the above described reaction with the organometallic ,r-zompound may also be brought about by the furthenaction of an excess of the organo-metallic2compoundat a raised temperature. Finally, the elimination ofpthe hydroxyl group or of the'halogen atom may alternatively be brought about by reductiomfomexample, by means of hydrogen in the presence of glacial acetic acid and a precious metal cetalyst. The conversion of the functionally converted carboxyl group in the 2- position into a free carboxyl group and/or of the esterifled or etherified hydroxyl group in the '7- position -into --'a;free hydroxyl group is brought about by hydrolysis; In the case of benzyl ether groups, there-.mayalso bemsed, for example, a reducingagent. An amino group in the 7-position .is convertedinto a hydroxyl group by diazotisation followed by boiling.-,.When the aforesaid substituents in the 2-'and 7-positions areboth to be converted into a free carboxyl groupand a free hydroxyl group, respectively, this may also be carbon multiple bonds, especially double or triple, j

bonds introduced by splitting oif the tertiary hydroxyl group or by reaction with an unsaturated organo-metallic compound, hydrogenation, if de-i sired, may be carried out at any stage after the reaction with the organo-metallic compound) For this purpose there may be used, for example, chemical methods such as catalytic or electrolytic hydrogenation or treatment with nascent hydrogen, or biochemical methods. A multiple bond of an unsaturated radical which has been introduced, and a double bond resulting from the.

splitting off of the tertiary hydroxyl group, may also be hydrogenated in tWo different reaction stages. More especially, a multiple bond introduced with an unsaturated radical may first be saturated with hydrogen, and then the tertiary hydroxyl group split ofi with the formation of a double bond, which is subsequently hydrogenated.

The resulting compounds containing free carboxyl groups may be esterified, for example, directly with diazomethane or diazo-ethane or indirectly by way of theacid chloride or an alkali salt of the carboxylicacid in question. Finally, free phenolic hydroxyl groups may be esterified or etherified in known manner. In this connection there maybe mentioned the esters with organic acids, especially with aliphatic and aromatic acids, for example, acetic acid, propionic acid, butyric acid, p'almitic acid, stearic acid or benzoic acid, or with 'sulphonic acids, polycarboxylic acids or carboxy-sulphonic acids, or finally with inorganic acids, such as sulphuric acid and phosphoric acid, or carbonic acid and derivaftiv'es thereof Q nmong the may be specially mentioned, for example, the alkyl others, such as the methyl, ethyl or propyl ethers, and the glucosides.

The free carboxylic acids may be converted into carboxylic acid salts, for example, alkali metal, alkaline earth metal or ammonium salts. When the ester or ether residues in the 7-position contain basic groups, the corresponding salts with example, may be made.

inorganic acids or the betaine ester salts, for g The said salts may be used in aqueous solution, or for inoculation therapy.

The products of the invention find application as medioaments or as intermediate products.

The starting materials used in the process of the invention are new. In order to'prepare them there may advantageously be used, for example, the following method of synthesis which is elucidated by the Formulae I to XII.

Reaction of the sodium salt of the malonic acid ester I with glutaric acid ester chloride yields the compound II, and then the triester IlIis obtained by ring closure, for example, with concentrated phosphoric acid or sulphuric acid. The dicarboxylic acid V, obtained by decarboxylation of the tricarboxylic acid IV (during which transposition of the ethylenic double bond occurs), is converted into the diester VI, which is then caused to undergo ring closure by the Block'- mann method to form the keto-ester VII. The desired l:2:3:4-tetrahydrofiuorene-l-one is obtained from VII, for example, by alkylation. By starting from the dicarboxylic acid IX and carrying out the last stages of the synthesis, there is obtained as the final product 1:2:3:4:10:11- hexahydrofluorene-l-one of Formula XII.

5i Suitable starting; nalsaahanealsorbesmbtamedsioreexample, in; the, iollowme: see'i mnnmlaeXIIL tmXVD-z v v Thea. hydroxymethylenelcompounrtgexlll 39h! tainedfromllzz;tirifletrahydnoflwrene:, one. i Formula XIII is reactedlwith hydmxlflaminel upon splitting oil water the compound XV is obtained. Alkyl'ation otthe latter compound yields the keto-nitrile XVI.

The following examplesillustrate the invention, the parts being by weight unless otherwise stated; andtherelations-hip-of parts by weightvto partsby-volume being'the same 'as that olE-Y: 5

gram to the cubic centimetre:

""Example 1 52A solution; 1015. 1 1 0, ;--paxtts;v ofi flremethoxyeia oxo-2-methyl- 1 :2 :3 4-tetrahydrofluorenea%ecam boxylic acid methyl ester of the formula 1.27; partsof mag-nesiumland"v 5;.1 pants bromide in 150 parts by volume of e thez: '.1 .v reaction mixture is then boiled on the water-bath and, after being cooled, is decomposed with ice and hydrochloric acid. After washing, drying and evaporating the solventythecrude reaction product is obtained in theiform at a brown coloured oil.

For the purpose of splittmgofi water; the prod- OhIOEOf-Olihllflihd, v aften-the additionoi 'Oilimar o9} iodine, is boiledi inqawrefiux apparatus water: ,:d-riedi" and." evaporated; 'Ihe1productsrea1o a lsmbe suiting.fromthezsplitting oil 'oflwater isaobtairred: instheifornnofr abrown colcmred;oil.s- After-Marile ti1lation:.;under meme-reduced::presstirei point-#1510? 6....1mden 0.05.;mm lzrzthereisnbta d pure lemethqxyszemethylelaethyiidsuee T 11. as benzene, toluenep acetic acid 6'. tetnahmm uerenel-zt-tearhe 01g lifmgmyl esterwoittheator v v I I v v :51CHI- --As-an--agent=for-splitting offi wateiethere isialso :suitable-, *--1'or exempla "concentratedrformic ag aid:

with-the-application ot'heat or phosphorus oxychloride in the presence of a suitable solvent such For the purpose of hydrolysing the carbomethoxy group,- ;$;-parts of '7-methoxy-2-methyll-ethylidene-l :2 :3 :4-tetrahydrofiuorene 2 carboxylic acid methyl ester are heated at 150-180 C. in a mixture of 25 pariszot. potassium hy ro ide, 5 parts by volume of water and 10 parts by r the as inglwitlrsuction h i the: with-ma fro cetone, The 'l-methox c1 areilmlte V 0.0 or;

IL CO -f melts at l51-152 C.

After recrystallisation from methanol, the '7- uct is then dissolved in 200*parts by volume 01 .2.6 &.methoxy-2 methylj= lethylel z2z3:4-tetrahydro ethyl ester, prepared 1 fluorene-2-carboxylicoiac from the above acidibysmeansrorgan ethereal solution of diam-methane, melts at 56-57 C.

The esterification of the carboxylcgmummaw earned out byz-v-tirstzlconvertine the acid mt dyantageouslymioraexe mulet by? means of xalylsachleride,aandereactmg fiber-aside rid .thr=.thezzdes.ired alceholv izeaetlzneetheeeaxboxylim with-salt withzam flin -7 s his upriate halide.

1 part of this hydroxy-acid'i's converted into the carbomethoxyde'rivative by means of diazo methane. The crude product is dissolved" in caustic soda solution, somewhat more than the calculated quantity of benzoylchloride is added, and the mixture is vigorously agitated. The benzoyl-derivative soon separates in the form of an oil. The resulting 7-benz oyloxy-=2-methyl-1- ethyl l:2z3z4-tetrahydrofluotene 2 carboxylic acid methyl ester boils at 180 C. under 0.05

pressure and has the formula In an analogous manner there can be obtained, for example, the 7-propionate and the 'I-butyrate.

By carrying out the synthesis with 'l-methoxy- 1-oxo-2-methyl-1:2:3:4:10:11 hexahydrofluo-' rene-2-carboxylic acid methyl ester of the for-- mula as starting material, the corresponding hexahydrofluorene derivatives, for example, 7-methoxy- 2-methyl-1-ethyl-152:3:4z10z11 hexahydrofluorene-z-carboxylic acid of the formula are obtained.

' In an analogous manner the synthesis may start with l-keto-hydrofiuorenes containing in the 7 -position a free hydroxyl group or an esterified hydroxyl group. such as a'benzyloxy, acetoxy or propionyloxy group and in the 2-position a nitrile or acid amide group. i

are converted in solution in benzene into the sodium compound by means of 3.45 parts of sodium. The sodium compound partially precipitates in crystalline form, and, after cooling, is reacted with 33 parts of glutaric acid ethyl ester chloride. In order to complete the reaction the whole is boiled for a further hour, and then cooled and poured into water. The benzene solution is washed with a solution of sodium chloride, dried and evaporated. The reaction product is purified by distillation under very reduced pressure (boiling point=182-l87 C. under 0.05 mm.) and has the formula o o 0 can,

COOCzHs C O 0 C 11,; H 60 ,i 3 'l --parts.of the latter keto triester are dissolvedin 250parts by volume of phosphoric acid of per cent. strength, and the mixture is heated for 5 hours at 50-60 C. The red-brown, clear solution, after being cooled, is poured into ice-water and extracted with ether. The red productlresulting-from ring closurehaving the formula a .1373, HaGO and mas at 233-235 0. (with Mascaras after recrystallisation from acetone. 32.6 parts of the latter acid are esterified by means of diazo-methane, and, in order to bring about theDieckmann condensation, the resulting oilydimethyl ester is heated in 320 parts by volume of benzene with sodium methoxide obtainedfrom 4.94 partsof sodium and methanol. After '24 hours the whole is cooled, a mixture of IIO' parts-by volume of. methyl iodide-and 110.

9 parts by volume of methanol is added, the whole is allowed to stand for 12 hours, and finally boiled for a further hour in -"areilu'xapparatus; "The cooled mixture is then poured"into"the-'ealculated quantity of ice-cold acetic acid, the solution is washed in turn with sodium carbonate solution and water, and evaporated-to-dryness. Themesi'due is distilled under very'reduced-ipresstirei The resulting '7-methoxy-1-oxo-2-methyl-1 :2 :3 :4-tetrahydrofluorene z cal boxylic acid-finethyl ester of the formula boils at 180 C. under 0.05mm.:pressure.flter recrystallisation from methanolit melts -ati 95 -In a similar manner it is '.-possible to introduce into the 2-position a hydrocarbon radical ofhigher molecular weight by using, instead of methyl can be obtained by a process similar to that described above and by hydrogcnating the ethylenic double bond in the course of the synthesis.

Example 2 5 parts of '7-methoxy-1-oxo-2-methyl-1:2:3:4- tetra-hydrofiuorene-Z-carboxylic acid methyl ester, dissolved in 75 parts by volume of benzene, are reacted at about C. with a Grignard solution prepared from 0.65 part of magnesium, 3.7 parts of methyl iodide and 75 parts by volume of ether. After subsequent boiling on the waterbath, the reaction mixture is worked up in the manner described in Example 1. The resulting crude reaction product is then dissolved in 50 parts by volume of formic acid of 90 per cent. strength, and heated at about 90 C. When the splitting off of water has ceased, the whole is poured into water, then taken up in ether, the ethereal solution is Washed with water and dried, and the solvent is evaporated. The residue is hydrolysed, without further purification, in .the manner described in Example 1. From the acid product of hydrolysis, obtained in the form of an oil, there crystallises 7-methoxy-2-methyl-1- methylene-1:2:3z4 tetrahydrofluorene 2-carboxylic acid melting at 125-127 C. with decomposition and having the formula C O OH it) "For the -'purpose'*-of --saturating-the semi-cyclic double bond -2.5 parts of the'foregoing unsaturated acid are dissolved in 500 parts by- -volume of" caustic soda solution of 1 per cent. strength and hydrogenated 'inthe presence of 5 parts of a nickel catalyst. The hydrogenation product,

*obtained in solid form by acidifying the alkaline solution, is recrystallised" from methanol, and

' consists of 7-methoxy-1:2-dimethly-1:2:3:4- tetrahydrofluorene-2-carboxylic acid melting at I'M-176 C. and having the formula By splitting off the methoxy group in the manner described in Example 1 there is obtained from the latter :product fl-hydroxy-lzZ dimethyl- 1 2 g3 z l-tetrahydrofluorene-2-carboxylic acid.

If, in -the;foregoingexamples, a higher alkylmagnesium halide is allowed to act on the l-ketohydrofluorenes, for example, on the '7-methoxy- 1-oxo-2-methyl-1 2 :3 :4 tetrahydrofluorene-Z- carboxylic acid methyl ester, there is obtained as the final product a tetrahydrofluorene having in the 1-position a corresponding higher alkyl substituent. In order to produce hydrofiuorenes having a substituent of higher molecular weight in the 2-position there is used as starting material a l-keto-hydrofiuorene having a substituent of higher molecular weight in the 2-position.

In a manner analogous to that described in the foregoing examples, there can be prepared v the following compounds:

I-methoxy-l-ethyl 2 benzyl 1:2:3z4 tetrahydrofluorene-2-carboxylic acid; 7-ethyoxy-lz2-dipropyl 112:3:4 tetrahydrofiuorene-Z-carboxylic acid ethyl ester; I-acetoxy l ethyl 2 methyl 1:2:3z4110z11- hexahydrofluorene-Z-carboxylic methyl ester; 7-hydroxy 1:2-diethyl 1:2:3:4:10:11 hexahydrofluorene-Z-carboxylic acid; 7-methoxy-1-ethyl-2-methy1 1:2:3z4 tetrahydrofiuorene-Z-carboXylic acid amide.

What we claim is:

l. A hydrofluorene containing a lower alkyl radical in each of the 1- and 2-positions, a member selected from the group consisting of the carboxylic acid and carboxylic acid ester groups with lower alkanols in the 2-position, and a member selected from the group consisting of phenolic hydroxyl, lower alkoxy and lower acyloxy in '7-posi-tion.

2. The 7-methoxy-1-ethyl-2-methyl 1:2:3:4- tetrahydrofluorene-Z-carb0xy1ic acid methyl ester of the formula -C 0 O CH:

and melting at about 56-57 G.

1 12 3. The 7-methoxy-1-e thyl-2-methyl 122:3:4-

izetrahydrofiuorene-z-carboxylic acid of the REFERENCES CITED formula, The following references are of record in the CH3 file of this patent:

UNITED STATES PATENTS C!H5 Number Name Date 2,429,166 Miescher et a1. Oct. 14, 1947 B300. 7. 10 OTHER REFERENCES Miescher: Helvetica. Chim. Acta, vol. 22, pp. and melting point at about 151-152 C. 1728, 1730, 1732, 1733 (1944).

4. The 7-hydroxy 1-ethy1-2-methy1-1z2z3z4- Heer et a1: Helvetica, Chim. Acta, Vol. 28, pp. tetrahydrofiuorene-Z-carboxylic acid of the l 1508, 1510 (1945). formula M5 Heer et 21.: Helvetic Chim. Acta., v01. 28, page Anner et a1: Helvetica Chim. Acta, v01. 30, pp. 1422, 1423, 1424, 1425 (1947). 09 Anner et a1: Helvetica. Chim. Acta, vol. 30, pp.

544, 545, 546, 547 (1947). Heer et a1: Helvetica Chim. Acta, Vol. 30, page 553 (1947). Heer et al.: Helvetica. Chim. Acta, Vol. 30, pp. and melting point at about 174-176 C. 25 7. 787 (1947) KARL MIESCHER.

GEORG ANNER.

. Certificate of Correction Patent No. 2,494,254 7 January 10, 1950 KARL MIESCHER ET AL.

It is hereby certified that errors appear in the printed specification of the above numbered patent requiring correction as follows:

Column 1, line 22, for the word estrongenic read estrogen'ic line 35, for hydronfluorene read hydrofluorene; lines 41 and 42, for organic-metallic read organo-.

metallic; columns 3 and 4, for the Roman numeral VII, second occurrence, designating the eighth formula, read VIII; column 5, line 2, after the word following insert manner; column 10, line 44, for that portion of the compound reading 7- e thyoxy-l read 'l-ethozy-I column 11, lines 12 and 25, after melting strike out point and that the said Letters Patent should be read with these corrections therein that the same may conform to the record of the case in the Patent Office.

Signed and sealed this 9th day of May, A. D. 1950.

[SEAL] THOMAS F. MURPHY,

Assistant flommz'sszi'aner 0! Patents. 

1. A HYDROFLUORENE CONTAINING A LOWER ALKYL RADICAL IN EACH OF THE 1- AND 2-POSITIONS, A MEMBER SELECTED FROM THE GORUP CONSISTING OF THE CARBOXYLIC ACID AND CARBOXYLIC ACID ESTER GROUPS WITH LOWER ALKANOLS IN THE 2-POSITION, AND A MEMBER SELECTED FROM THE GROUP CONSISTING OF PHENOLIC HYDROXYL, LOWER ALKOXY AND LOWER ACYLOXY IN 7-POSITION. 